Spherical crystal agglomeration of ibuprofen by the solvent‐change technique in presence of methacrylic polymers

Journal of Pharmaceutical Sciences (Impact Factor: 2.59). 02/2000; 89(2):250 - 259. DOI: 10.1002/(SICI)1520-6017(200002)89:2<250::AID-JPS12>3.0.CO;2-W
ABSTRACT
The effects of Eudragit® nature on the formation and spherical agglomeration of ibuprofen microcrystals have been examined when solvent change (ethanol-water) technique is applied. Four methacrylic polymers (Eudragit® S100, L100, RS, and RL), with different solubility and solubilizing ability, were used. The extrapolated points of maximum temperature deviation rate in crystallization liquid that reflect the maximum crystallization rate and the corresponding water addition were determined, as well as crystal yielding and incorporation of drug and polymer in the agglomerates. The physicomechanical properties of the agglomerates, such as size, sphericity, surface roughness and porosity, as well as flow and packing or compression behavior during tableting, were evaluated for different drug/polymer ratios. It was found that crystal yield is greatly reduced in the presence of water-insoluble polymers and that formation of the microcrystals and incorporation of drug and polymer are affected by the polymer nature. Crystal formation changes are attributed to alterations in the metastable zone, whereas the changes in drug and polymer incorporation and crystal yield are caused by changes in the polymers' solubility and micellization. The size of agglomerates depends on the polymer nature and its interactions with the ibuprofen microcrystals formed. Sphericity, surface roughness, and intraparticle porosity of agglomerates increase, in general, with the presence of polymer owing to changes in habit and growth rate of the microcrystals and to their coating before binding into spherical agglomerates. The particle density or intraparticle porosity and size changes determine flow or packing behavior and densification of agglomerates at low compression. The incorporation and brittleness of the polymer determine the deformation under higher compression pressure, expressed as yield pressure, Py.

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Spherical Crystal Agglomeration of Ibuprofen by the
Solvent-Change Technique in Presence of
Methacrylic Polymers
KYRIAKOS KACHRIMANIS, IOANNIS NIKOLAKAKIS, STAVROS MALAMATARIS
Laboratory of Pharmaceutical Technology, School of Pharmacy, University of Thessaloniki, Thessaloniki 54006, Greece
Received 25 June 1999; accepted 12 November 1999
ABSTRACT: The effects of Eudragitnature on the formation and spherical agglomera-
tion of ibuprofen microcrystals have been examined when solvent change (ethanol-
water) technique is applied. Four methacrylic polymers (Eudragit S100, L100, RS, and
RL), with different solubility and solubilizing ability, were used. The extrapolated
points of maximum temperature deviation rate in crystallization liquid that reflect the
maximum crystallization rate and the corresponding water addition were determined,
as well as crystal yielding and incorporation of drug and polymer in the agglomerates.
The physicomechanical properties of the agglomerates, such as size, sphericity, surface
roughness and porosity, as well as flow and packing or compression behavior during
tableting, were evaluated for different drug/polymer ratios. It was found that crystal
yield is greatly reduced in the presence of water-insoluble polymers and that formation
of the microcrystals and incorporation of drug and polymer are affected by the polymer
nature. Crystal formation changes are attributed to alterations in the metastable zone,
whereas the changes in drug and polymer incorporation and crystal yield are caused by
changes in the polymers’ solubility and micellization. The size of agglomerates depends
on the polymer nature and its interactions with the ibuprofen microcrystals formed.
Sphericity, surface roughness, and intraparticle porosity of agglomerates increase, in
general, with the presence of polymer owing to changes in habit and growth rate of the
microcrystals and to their coating before binding into spherical agglomerates. The
particle density or intraparticle porosity and size changes determine flow or packing
behavior and densification of agglomerates at low compression. The incorporation and
brittleness of the polymer determine the deformation under higher compression pres-
sure, expressed as yield pressure, Py.
© 2000 Wiley-Liss, Inc. and the American Pharmaceu-
tical Association J Pharm Sci 89: 250–259, 2000
INTRODUCTION
Ibuprofen [2-(4-isobutylphenyl)propionic acid] is
a nonsteroidal anti-inflammatory drug that is
used in high doses (200–800 mg every 4–6 hours).
The danger for occurrence of adverse effects after
oral delivery of ibuprofen is significant because of
its specific biologic characteristics (rapid absorp-
tion, high [more than 80 %] bioavailability, and
short [2.0 ± 0.5 hours] biologic half-life).
1
There-
fore, interest in sustained, or enteric-release, oral
dosage forms of ibuprofen is justified.
Methacrylic copolymers (Eudragit) are offered
in a variety of types with different water solubil-
ity and permeability properties and have been
used for drug release modification in several oral
solid dosage forms.
2–5
Eudragit S100 and L100
have pH-dependent solubility in water, whereas
Eudragit RS and RL are insoluble but water per-
meable. Because EudragitL100 is soluble at pH
> 6 and S100 at pH > 7, both are used as enteric
Correspondence to: S. Malamataris. (E-mail: smalam@
pharm.auth.gr)
Journal of Pharmaceutical Sciences, Vol. 89, 250–259 (2000)
© 2000 Wiley-Liss, Inc. and the American Pharmaceutical Association
250 JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 89, NO. 2, FEBRUARY 2000
Page 1
coating materials resistant to the gastric fluid.
6
Eudragit RS is slightly water permeable,
whereas RL is freely permeable to water because
of higher content of quaternary ammonium
groups. Both EudragitRS and RL, therefore, are
used for the production of sustained-release for-
mulations.
7
For the enteric release of ibuprofen
the preparation of spherical crystal agglomerates
with Eudragit S100 has been suggested by ap-
plying the solvent change technique, and recently
the effects of crystallization conditions on their
physicomechanical properties have been investi-
gated.
8–10
It was found that the fundamental ag-
glomerate properties are affected by changes in
the habit and growth of ibuprofen crystals caused
by the presence of polymer.
10
Spherical crystallization was defined as an ag-
glomeration technique that directly transforms
crystals into a compacted spherical form during
the crystallization process.
11
Until now two main
variations of this technique have been applied:
the spherical agglomeration (SA) and the quasi-
emulsion solvent diffusion (QESD). Modifications
have been suggested for specific drug formulation
purposes.
12,13
Because habit of microcrystals and
their growth and agglomeration may be affected
by the conditions of spherical crystallization, as
well as by the presence of polymer added as a
binder, it was of interest to examine the effects of
Eudragiton the formation and agglomeration of
ibuprofen microcrystals.
In this study we compare the crystallization
parameters and the physicomechanical proper-
ties of spherical crystal agglomerates when the
solvent change (ethanol-water) technique is ap-
plied in the presence of methacrylic (Eudragit)
polymers of different solubility and solubilizing
ability.
EXPERIMENTAL SECTION
Materials
Crystalline ibuprofen (USP grade, from Boots
Pharmaceuticals, Nottingham, England, supplied
by Vianex, Athens, Greece) and four methacrylic
copolymers in powder form (Eudragit S100,
L100, RS, and RL, supplied by Ro¨hm Pharma,
Darmstadt, Germany) were used as main con-
stituents. Water distilled by an all-glass appara-
tus and analytical grade absolute ethanol (Merck,
Darmstadt, Germany) were used as poor and good
solvent, respectively. Mercury (Merck, Darm-
stadt, Germany) was used as the displacement
liquid for the porosity determination. Because
Eudragit S100 and L100 have pH-dependent
solubility, the pH of the distilled water was mea-
sured and was found to be 5.96 ± 0.01.
Preparation of Spherical Crystal Agglomerates
Sixteen batches of spherical crystal agglomerates
were obtained by using each type of polymer at
four drug/polymer ratios: 35 : 8, 50 : 8, 65 : 8, and
80:8gandonebatch by using 80 g of ibuprofen
in the absence of polymer (reference sample). The
amounts of ibuprofen, ethanol, and water used
were selected for maximal yield of agglomerates,
after determination of ibuprofen solubility in dif-
ferent mixtures of water and 8% w/w ethanolic
polymer solution, at the mean crystallization tem-
perature (30°C, Fig. 1).
For the determination of ibuprofen solubility in
the presence of the polymers, excess ibuprofen
powder was dispersed in the mixtures of water
and ethanolic polymer solutions. After shaking
for 72 hours at 30°C, aliquots of the supernatant
solution were filtered by positive pressure. The
filtrates, after appropriate dilution, were assayed
spectrophotometrically. These results, Figure 1,
show the solubilizing ability of polymers and may
allow elucidation of the effect of their presence on
Figure 1. Solubility of ibuprofen in different mix-
tures of water and 8% w/w ethanolic polymer solutions,
at 30°C: , S100; , L100; ,RS;, RL; and , refer-
ence sample.
AGGLOMERATION OF IBUPROFEN 251
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 89, NO. 2, FEBRUARY 2000
Page 2
the supersaturation of the crystallization medium
as well.
For the preparation of spherical crystal ag-
glomerates, an apparatus described previously
was used.
10
The applied procedure was as follows:
Specified amounts of crystalline ibuprofen (35–80
g) and 8.0 g of polymer were dissolved in 100 g of
ethanol, kept under constant agitation (600 rpm)
and temperature (50°C), inside a 1000-ml (7 × 30
cm) crystallization vessel. Subsequently, distilled
water (700 ml) was added at a constant rate (5.9
ml/min), whereas cooling was applied from 50°C
down to 10°C with a programmable refrigerated
circulator (0.33°C/min). The temperature of the
crystallization liquid was recorded, and extrapo-
lated points of maximum temperature deviation
rate were determined together with the corre-
sponding water consumption as parameters of
maximum crystallization rate.
The agglomerates produced were collected by
vacuum filtration, dried at 50°C in a vacuum
oven, and kept in screw-capped, amber glass jars.
Crystal yield was calculated from the weight of
agglomerates and their drug content. The varia-
tion of drug content in five sieve-fractions of dif-
ferent size was determined as well. In addition,
the physicomechanical properties that may affect
the quality of tablets and capsules produced from
spherical crystal agglomerates, such as the mi-
cromeritic properties (size and size distribution,
shape, surface roughness, density, and porosity),
the flow or packing, and the compression behavior
were assessed.
Characterization of Spherical Crystal Agglomerates
Size was evaluated as geometric mean diameter
(d
g
) and size distribution as geometric standard
deviation (
g
). These values were determined by
sieve analysis, after plotting cumulative under-
size weight percentage on a log-probability scale
versus sieve size on a logarithmic scale. The size
corresponding to 50% cumulative undersize is d
g
,
and
g
is the size ratio of 84.13 : 50% undersize.
Shape and surface roughness were quantified as
roundness and fractal dimension (D
f
), respec-
tively, by using an image processing and analysis
system (Quantimet 500, Leica, Cambridge, En-
gland). Roundness is the square of perimeter di-
vided by 12.56 times the projection area and as-
sumes a value of 1 for a sphere. Fractal dimension
(D
f
) was determined with a successive dilation se-
quence from the slope of logarithmic plots of pe-
rimeter length versus measuring unit (“Richard-
son” plots) as: D
f
1 + |slope|.
14
In addition,
scanning electron photomicrographs were taken
to see the morphology and structure of the ag-
glomerates. Density was determined as true,
loose bulk and tapped density. Porosity was mea-
sured using the pyknometric method of Strick-
land.
15
Intrusion pressures between 360 and 1200
mm Hg were applied, which correspond to a pore
diameter range of about 40 to 12 m. The follow-
ing parameters were calculated: the particle den-
sity; the interparticle and intraparticle porosity;
the fraction of pores with diameter 40 to 12 m
and <12 m; and the mean pore diameter.
The flow behavior was quantified as compress-
ibility index (C.I. %) and angle of repose. The com-
pression behavior was expressed as parameters
in Heckel’s equation (densification at low pres-
sure, D
B
, and yield pressure, P
y
) determined with
an instrumented single punch tableting machine.
All the equipment and methods used for the char-
acterization of spherical crystal agglomerates
have been described previously.
10
RESULTS AND DISCUSSION
Crystallization Parameters
The crystal yield results given in Table I show
significant alterations caused by changes either
in the nature of polymer added or in the drug/
polymer ratio applied. Small reductions in crystal
yield (<10%), similar to that of the reference
sample, correspond to the cases of water-soluble
polymers (S100 and L100), which reduce the ibu-
profen solubility in ethanol/water mixtures (Fig.
1). On the contrary, in the cases of water-insol-
uble polymers (RS and RL) that increase the ibu-
profen solubility in ethanol/water mixtures, there
is a significant reduction in crystal yield, particu-
larly at the lower drug/polymer ratios.
Solubilization of ibuprofen by Eudragit RS
and RL, shown in Figure 1, can be attributed to
electrostatic interactions with the quaternary
ammonium groups existing in their molecules, al-
ready reported for other acidic pharmaceutical
compounds.
16
The amounts of ibuprofen and polymer lost in
the crystallization liquid were calculated from the
weight of agglomerates produced and their drug
content (Table I). These losses are small and al-
most independent of the amount of drug added
initially (supersaturation ratio), when the water-
soluble polymers (S100 and L100), which de-
crease the solubility of ibuprofen (Fig. 1), are
252 KACHRIMANIS, NIKOLAKAKIS, AND MALAMATARIS
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 89, NO. 2, FEBRUARY 2000
Page 3
added. On the contrary, losses increase and are
inversely related to the amount of drug added,
with the water-insoluble polymers (RS and RL),
which enhance drug solubility (Fig. 1). The distri-
bution of the constituents (drug and polymer) is
independent of the agglomerates’ size because the
coefficient of drug content variation, C.V. %, be-
tween the sieve-fractions was found to be less
than 3.5% (Table I). Therefore, the reduction in
the crystal yield must be caused by the relative
losses of polymer and ibuprofen.
Massive crystal formation is completed long be-
fore the end of cooling or water addition, as is
evident from the temperature plots (Fig. 2). Also,
the increase of ibuprofen solubility in the pres-
ence of RS and RL (Fig. 1) cannot explain the
great extent of yield reduction observed. There-
fore, the most probable explanation is colloidal
dispersion of both ibuprofen and polymer in the
crystallization medium in addition to the dissolu-
tion.
Opacity of the crystallization liquid was ob-
served after the collection of the agglomerates by
filtration for the cases of water-insoluble Eudra-
gitRS and RL at low drug/polymer ratios (35 : 8
and 50 : 8). Therefore, reduction of polymer solu-
bility caused by the water addition and excess of
critical micelle concentration (CMC) may lead to
formation of micelles of Eudragit RS and RL
polymers because of the existence of quaternary
ammonium groups in their molecules. Subse-
Table I. Crystallization Parameters for Ibuprofen Spherical Crystal Agglomerates Prepared with Different
Eudragit and Increasing Drug/Polymer Ratio
Eudragit Type and
Drug/Polymer
Ratio (g/g)
Crystal
Yield (%)
Drug
Content
(% w/w)
±(CV%)
a
Drug
Lost (g)
Polymer
Lost (g)
Point of Maximum
Temperature
Deviation Rate
(°C)
Water
Consumption
(ml)
80/0 94.3 100 (1.1) 4.6 0.0 36.1 290
S100 35/8 90.5 84.0 (0.1) 2.3 1.8 33.8 296
50/8 92.8 88.3 (0.3) 2.5 1.7 32.6 304
65/8 95.9 91.5 (0.9) 2.0 1.8 35.6 290
80/8 95.2 93.0 (3.4) 2.1 2.1 35.6 292
L100 35/8 91.2 85.0 (3.0) 1.7 2.1 32.0 312
50/8 95.2 89.0 (1.9) 1.9 1.9 36.7 (32.0)
b
272
65/8 95.5 90.0 (0.7) 2.3 1.0 38.6 (36.3)
b
245
80/8 91.8 91.0 (1.4) 2.5 0.7 39.5 (37.2)
b
228
RS 35/8 43.3 91.0 (1.1) 12.7 5.8 31.7 320
50/8 57.0 92.0 (1.1) 26.9 6.0 31.7 320
65/8 88.9 93.0 (0.7) 4.6 3.5 35.1 316
80/8 91.9 95.5 (1.0) 2.7 4.4 34.9 285
RL 35/8 64.2 98.0 (3.5) 7.9 7.4 31.7 350
50/8 78.0 98.0 (0.8) 5.7 7.1 31.7 350
65/8 80.1 96.5 (0.7) 8.5 5.9 30.8 332
80/8 87.5 96.0 (1.7) 6.1 4.9 33.3 320
a
CV% coefficient of variation for drug content in five sieve fractions.
b
Second extrapolated onset of temperature deviation.
Figure 2. Typical temperature versus time plots of
the crystallization liquid corresponding to different
Eudragit polymers, at drug/polymer ratio 80/8 g (poly-
mer: a, none (reference sample); b, S100; c, L100; d, RS;
and e, RL).
AGGLOMERATION OF IBUPROFEN 253
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 89, NO. 2, FEBRUARY 2000
Page 4
quent engulfing of ibuprofen by the micelles could
be the reason for the great increase in drug loss,
particularly in the case of Eudragit RS. The
amount of water required for the separation of the
polymers from solution (appearance of permanent
turbidity) and the temperature at which this oc-
curred in the absence of ibuprofen (blank solu-
tion) were determined and the results are pre-
sented in Table II. It is seen that the amount of
water is reduced in the order L100 > S100 > RL >
RS, or for the less water-soluble polymers turbid-
ity appears at higher temperature and smaller
amount of water as expected.
Figure 2 shows typical temperature versus
time plots for the crystallization liquid of different
polymers at a certain drug/polymer ratio (80:8g).
Straight dotted lines correspond to the pro-
grammed temperature and the positive deviation
is due to heat released during crystallization of
ibuprofen. Onset and endset points should indi-
cate initiation and cessation of massive crystalli-
zation, respectively, whereas the point of maxi-
mum temperature deviation rate corresponds to
maximum crystal growth rate (i.e., to maximum
supersaturation ratio). For the case of Eudragit
L100, two maxima of temperature deviation ap-
pear at two different combinations of temperature
and water consumption. This can be attributed to
great enhancement in the formation of ibuprofen
microcrystals. In other words, faster release of la-
tent heat of crystallization and quick increase in
the temperature of the crystallization liquid
causes an increase in the solubility of ibuprofen,
thus slowing down the formation and growth of
crystals at this low water addition level. Subse-
quently, when the reduction of ibuprofen solubil-
ity caused by water addition is smaller (Fig. 1)
and the released latent heat of crystallization is
controlled by the cooling system, the rate of crys-
tal formation increases again and attains a sec-
ond (final) maximum because of reduction in the
amount of ibuprofen.
Two maxima of temperature deviation, as seen
with L100, might also be expected for the case of
Eudragit S100 because it also reduces the solu-
bility of ibuprofen. However, a single maximum is
observed instead. The reason for this difference
may lie either in the lower solubility of S100 re-
sulting in a greater amount of solvent being avail-
able to interact with ibuprofen at the crystalliza-
tion point or in less hydrogen bonding between
carboxylic groups of polymer and drug. Compared
with S100, L100 contains twice the amount of free
carboxyl groups, which are hydrogen bond donors
and acceptors as well.
The area under the curve (AUC) of the tem-
perature deviation plots (Fig. 2) did not indicate
any change in crystal formation caused by the
presence of polymer. This is because in addition to
the level at which temperature deviation occurs,
the AUC is also affected by the cooling capacity of
the system used. Therefore, the AUC results show
only the expected increase caused by the amount
of ibuprofen added in the crystallization solution
(initial supersaturation). Furthermore, the initial
supersaturation affects the point of maximum
rate in temperature deviation and the water con-
sumption. The alteration in the formation of the
crystals caused by the presence of the polymer is
evident from the extrapolated point of maximum
temperature deviation rate and from the corre-
sponding water consumption (Table I) when cer-
tain amounts of ibuprofen and polymer are added
(80 : 8 g). This point, in the case of the reference
sample, is higher, and the corresponding water
consumption is lower compared with those for the
samples prepared in presence of polymer, except
in the case of Eudragit L100. Furthermore, the
changes of the extrapolated point of maximum
temperature deviation rate and of corresponding
water consumption for the different polymers
used are in parallel to those of the alteration in
the solubility of ibuprofen (Fig. 1).
Considering that initiation of crystallization
occurs when the supersaturation ratio reaches a
critical value because of cooling and water addi-
tion, all the aforementioned alterations in crys-
tallization parameters confirm that this value is
determined by both the amount of ibuprofen and
the nature of polymer (type of Eudragit). In
other words, they indicate that the type of Eudra-
gitaffects the solubility of ibuprofen and the su-
persaturation ratio or the width of the metastable
zone.
17
Table II. Temperature and Water Addition for
Appearance of Turbidity in Ethanolic Solutions of 8%
w/w Eudragit Polymers (n 3)
Polymer
Type
Temperature
(°C ± SD)
Amount
of Water
(ml±SD)
Ethanol/Water
Ratio (w/w)
L100 42.3 ± 0.2 138.2 ± 1.6 1:1.38
S100 45.2 ± 0.3 85.3 ± 2.5 1:0.85
RL 46.2 ± 0.2 68.7 ± 1.3 1:0.68
RS 46.9 ± 0.1 55.0 ± 2.0 1:0.55
254
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JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 89, NO. 2, FEBRUARY 2000
Page 5
Physicomechanical Properties
From the size results (Table III) it can be seen
that d
g
of ibuprofen alone (reference sample) is
slightly higher than that of agglomerates pre-
pared in the presence of polymers, with the same
amount of ibuprofen (ibuprofen/polymer 80:8g),
except in the case of Eudragit RL. Also, the re-
sults in Table III show that, in general, d
g
in-
creases with increasing drug/polymer ratio for the
cases of L100 and RL but decreases in the cases of
S100 and RS, with the exception of S100 at low
drug/polymer ratio (35 : 8). Furthermore,
g
for
all the agglomerates prepared in the presence of
polymer is lower than that of the reference
sample, except in the cases of water-soluble poly-
mers (S100) at low drug/polymer ratio (35 : 8),
indicating the presence of large and small ag-
glomerates in smaller proportion.
Agglomeration is known to increase with in-
creasing supersaturation because increased su-
persaturation leads to higher nucleation rates
and to a higher concentration of microcrystals.
This in turn leads to the aggregation of the mi-
crocrystals, which facilitates the extensive bind-
ing of the aggregates into agglomerates. Table II
shows that the polymer solubility decreases at
temperatures higher than the crystallization
point of ibuprofen in Table I. Therefore, assuming
that the separated polymer facilitates agglomera-
tion of the developed ibuprofen microcrystals and
that ibuprofen added in higher amounts increases
the number of microcrystals and, therefore, the
frequency of collisions, an increase in d
g
is ex-
pected with increases in the amount of both ibu-
profen and polymer. The unexpected size de-
crease of agglomerates in the presence of poly-
mers and with increasing drug/polymer ratio may
be attributed to changes in the habit and size of
ibuprofen microcrystals caused by polymer pres-
ence. Also, the decrease of d
g
, with decreasing
mass fraction of S100 and RS, may indicate that
their binding ability is adequate to counteract the
effect of increased frequency of collisions caused
by the addition of ibuprofen. On the contrary, the
polymers RL and L100 should have smaller bind-
ing ability. So, the effect of frequency of collisions
is predominant. The great difference in agglom-
erate size between L100 and RL confirms the ef-
Table III. Micromeritic Properties and Flow Parameters of Ibuprofen Spherical Crystal Agglomerates Prepared
with Different Eudragit and Increasing Drug/Polymer Ratio
Eudragit Type
and Drug/Polymer
Ratio (g/g)
Particle Size
Particle Shape
(n 200)
Density (g/ml)
(n 3)
Compressibility
Index (%)
Angle of
Repose
d
(°)d
g
(m)
g
Roundness
a
Df
b
Bulk
c
Tapped
c
80/0 1150 0.652 7.9 1.07 0.39 0.45 13.2 58.5
S100 35/8 1110 0.806 2.7 1.19 0.32 0.35 7.9 34.5
50/8 2000 0.650 2.8 1.26 0.36 0.39 5.4 34.5
65/8 1910 0.492 4.4 1.26 0.26 0.28 8.1 41.0
80/8 975 0.482 7.6 1.22 0.27 0.31 11.9 44.0
L100 35/8 550 0.672 3.3 1.26 0.19 0.23 17.2 34.5
50/8 725 0.589 4.6 1.26 0.21 0.25 16.7 45.0
65/8 760 0.559 5.5 1.25 0.24 0.28 12.2 21.0
80/8 810 0.493 7.3 1.23 0.23 0.28 16.8 34.5
RS 35/8 1400 0.464 2.6 1.25 0.26 0.29 10.8 55.5
50/8 1250 0.400 3.8 1.27 0.25 0.30 14.2 54.5
65/8 1200 0.491 3.9 1.29 0.24 0.27 12.4 55.5
80/8 1100 0.436 5.0 1.30 0.24 0.28 12.7 42.5
RL 35/8 1430 0.419 3.9 1.18 0.26 0.32 14.2 58.0
50/8 1490 0.463 5.9 1.21 0.25 0.30 15.9 56.0
65/8 1700 0.486 6.5 1.18 0.23 0.28 14.1 48.0
80/8 1850 0.397 7.2 1.16 0.26 0.30 13.2 50.5
a
SD<1.0.
b
SD < 0.05.
c
SD<0.1.
d
SD<2.0.
AGGLOMERATION OF IBUPROFEN
255
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 89, NO. 2, FEBRUARY 2000
Page 6
fect of supersaturation. Supersaturation should
be accelerated as a result of the decrease of ibu-
profen solubility by L100, and the size of micro-
crystals should be smaller and the collisions
weaker. Therefore, we can conclude that the effect
of polymer on the agglomerate size depends on its
nature and the interactions with the ibuprofen
microcrystals formed.
The shape results (Table III) show that round-
ness of all the spherical agglomerates prepared in
the presence of polymer is lower and fractal di-
mension, D
f
, is greater than the value of the ref-
erence sample. Taking into account that lower
roundness value means greater sphericity,
whereas higher fractal dimension means in-
creased surface roughness, we can say that the
presence of polymer contributes to improved
sphericity and increased surface roughness of the
agglomerates. Also, the roundness results (Table
III) show that sphericity, in general, is improved
with the increase in the mass fraction of polymer.
Improvement of sphericity may be attributed
to coating of the microcrystals before their bind-
ing into agglomerates, which can result in im-
proved symmetry of packing and equal agglomer-
ate dimensions. The increase in surface rough-
ness should be attributed to changes of habit and
packing of the microcrystals developed. SEM pho-
tomicrographs show loose structure of acicular
microcrystals for the reference sample [Fig. 3(a)],
closer and continuous packing of tabular micro-
crystals for S100 and L100 [Fig. 3(b) and (c)], and
discontinuous arrangement of prismatic ibupro-
fen microcrystals and particles for the water-
insoluble RS or RL polymers [Fig. 3(d) and (e)].
The flow parameters (Table III) show that the
bulk and tapped density of all the spherical crys-
tal agglomerates prepared in presence of any type
of Eudragit is lower than that of the reference
sample, although their sphericity is higher and
their size is greater for most cases. Therefore, the
reduction in bulk and tapped density should be
related to the intraparticle porosity or particle
density (Table IV) and to the surface roughness.
As far as compressibility index, C.I. %, and the
angle of repose values are concerned (Table III), it
is seen that the last are smaller for all the cases of
agglomerates prepared in the presence of polymer
than those of the reference sample. The C.I. %
values are lower than those of the reference
sample, except in the cases of Eudragit L100 and
RL for almost any drug/polymer ratio. The de-
crease in the angle of repose is probably due to
improved sphericity, and the increase of C.I. % for
the latter cases should be attributed to the
smaller particle size (for L100) and to the rela-
tively small improvement in sphericity (for the
RL case mentioned previously).
Regarding the density and porosity results
(Table IV), it can be seen that true density values
are higher and particle density values are lower
than that of the reference sample, except in the
case of Eudragit S100 at low drug/polymer ratio
(35 : 8). The increase in true density of agglomer-
ates is expected because for all the methacrylic
polymers used the true density is greater (1.2–1.5
g/ml) than that of ibuprofen (1.1 g/ml). In con-
trast, the lower particle density of agglomerates
relative to that of the reference sample (Table IV)
should be attributed to the increased intrapar-
ticle porosity.
Intraparticle porosity,
intra
, given in Table IV,
is generally higher than that of the reference
sample, except for S100 in a low drug/polymer
ratio (35 : 8), whereas interparticle porosity,
inter
,
shows positive and negative deviations (30%).
The increase in intraparticle porosity corresponds
to pores with diameter between 40 and 12 mor
smaller than 12 m. Only for the agglomerates
prepared in presence of Eudragit RS and those
prepared with Eudragit RL in a high drug/
polymer ratio (80 : 8) is the proportion of small
pores,
<12
, lower than that of the reference
sample. No correlation was observed between the
intraparticle porosity and the drug/polymer ratio,
except in the case of Eudragit S100 in which
intraparticle porosity increases with drug/
polymer ratio. The mean pore diameter is larger
than that of the reference sample in almost all the
cases of agglomerates prepared in presence of
Eudragit polymers.
The increase of pore diameter in combination
with the increase in intraparticle porosity caused
by the polymer indicates the absence of polymer
deposition in the empty spaces between micro-
crystals in the agglomerates. Therefore, these in-
creases should be attributed to coating and habit
alteration of the ibuprofen microcrystals compris-
ing the agglomerates. Coating is probably devel-
oped before binding into spherical agglomerates,
leading to greater resistance of rearrangement
and looser packing after collisions.
The compression behavior of the spherical ag-
glomerates is expressed as parameters of the
Heckel equation,
18
namely, the increase in pack-
ing density at the early stages of compression, D
B
,
and the yield pressure, P
y
, given in Table IV. Also,
representative Heckel plots are shown in Figure
256 KACHRIMANIS, NIKOLAKAKIS, AND MALAMATARIS
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 89, NO. 2, FEBRUARY 2000
Page 7
4. D
B
has been obtained from the difference be-
tween the packing fraction corresponding to the
intercept of the extrapolated intermediate linear
part of Heckel plots (Fig. 4) and that correspond-
ing to tapped density. The yield pressure, P
y
,is
the reciprocal of the slope in the linear part cor-
responding to pressure range between 20 and 80
MPa.
From the results in Table IV, it is seen that D
B
,
for all the agglomerates prepared in presence of
polymer, is higher than that of the reference
sample, except in the case of S100 with low drug/
polymer ratio (35 : 8 and 50 : 8 g). Also, the in-
crease of D
B
does not seem to be related to sphe-
ricity and surface roughness changes. Therefore,
it should be related to particle size and particle
density or intraparticle porosity. The yield pres-
sure for all the agglomerates prepared in the
presence of polymer is higher than that of the
reference sample, except for the case of Eudragit
Figure 3. SEM photomicrographs of spherical crystal agglomerates prepared in pres-
ence of different Eudragit polymers at drug/polymer ratio 80/8 g (key as in Figure 2).
AGGLOMERATION OF IBUPROFEN 257
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 89, NO. 2, FEBRUARY 2000
Page 8
RS and RL at high drug/polymer ratio (65:8and
80 : 8). For the last cases the polymer loss is great
and the yield pressure, P
y
, is similar to that of the
reference sample. Furthermore, the yield pres-
sure, P
y
, in general, increases with the mass frac-
tion of the polymer.
The brittleness and the incorporation of the
polymer should determine the increase of yield
pressure. It is known that Eudragit L100 and
S100 are less plastic and more brittle than ibu-
profen and EudragitRS and RL. Brittle fracture
indexes reported in literature are 1.60 for L100,
1.20 for S100, and 0.07 for RL and RS,
19
whereas
that for ibuprofen is 0.06.
20
CONCLUSIONS
From the preceding it can be concluded that when
solvent-change technique is applied with ethanol
and water as miscible solvents for the spherical
crystal agglomeration of ibuprofen in presence of
methacrylic (Eudragit) polymers the following
apply:
(a) Crystal formation and growth changes oc-
cur because of alterations of the metastable
zone caused by solubility changes, whereas
the incorporation of drug and polymer into
Figure 4. Heckel plots of spherical crystal agglomer-
ates prepared in presence of different Eudragit poly-
mers at drug/polymer ratio 35/8 g (key as in Figure 1).
Table IV. Parameters of Porosity and Compression Behavior (Heckel’s Equation) for Ibuprofen Spherical
Crystal Agglomerates Prepared with Different Eudragit and Increasing Drug/Polymer Ratio (n 3)
Eudragit Type
and Drug/Polymer
Ratio (g/g)
Density (g/ml) Porosity (%)
Pore Mean
Diameter
(m)
Heckel Parameters
D
B
b
P
y
(MPa)
(mean ± SD)True
a
Particle
a
inter
intra
40–12
<12
80/8 1.076 0.733 51.9 31.9 21.7 10.2 16.0 0.412 20.2 ± 3.1
S100 35/8 1.116 0.791 55.7 29.1 17.5 11.6 18.0 0.373 49.7 ± 9.6
50/8 1.109 0.729 46.5 34.3 20.0 14.3 17.0 0.373 54.1 ± 6.4
65/8 1.106 0.632 55.7 42.8 26.9 15.9 18.5 0.511 47.3 ± 9.4
80/8 1.085 0.618 49.8 44.1 29.8 14.3 18.0 0.495 30.6 ± 4.8
L100 35/8 1.113 0.635 63.8 42.9 28.3 14.6 19.0 0.481 51.2 ± 8.0
50/8 1.103 0.596 56.7 55.0 34.8 20.2 14.5 0.563 57.1 ± 8.8
65/8 1.081 0.632 55.7 41.5 29.0 12.5 19.5 0.478 36.9 ± 8.5
80/8 1.094 0.612 54.2 44.1 27.7 16.4 20.0 0.471 37.3 ± 9.4
RS 35/8 1.091 0.695 58.3 36.3 33.6 2.7 19.5 0.517 38.6 ± 8.5
50/8 1.080 0.682 61.6 37.6 25.9 11.7 20.0 0.485 25.9 ± 2.9
65/8 1.085 0.634 57.4 41.5 35.3 6.2 18.0 0.470 21.2 ± 2.9
80/8 1.081 0.682 64.2 37.7 27.6 10.1 18.0 0.536 24.8 ± 5.3
RL 35/8 1.101 0.450 38.9 59.2 21.1 38.1 17.0 0.577 48.6 ± 9.3
50/8 1.091 0.539 44.3 50.6 20.1 30.5 16.5 0.549 35.9 ± 8.1
65/8 1.083 0.486 42.4 55.2 21.4 33.8 17.0 0.465 18.6 ± 2.2
80/8 1.080 0.682 46.0 36.8 31.9 4.9 19.0 0.474 17.2 ± 1.2
a
SD < 0.001.
b
SD<0.1.
258 KACHRIMANIS, NIKOLAKAKIS, AND MALAMATARIS
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 89, NO. 2, FEBRUARY 2000
Page 9
agglomerates and the crystal yield are al-
tered by the polymer’s solubility and mi-
cellization.
(b) The effect on the agglomerates’ size de-
pends on the nature of the polymer,
whereas sphericity, surface roughness, and
intraparticle porosity increase, in general,
with the polymer presence because of
changes in habit and growth rate of ibupro-
fen microcrystals and to their coating be-
fore binding into spherical agglomerates.
(c) Flow behavior and densification of agglom-
erates at low compression are determined
by the particle density or intraparticle po-
rosity and size changes, whereas their de-
formation under higher compression pres-
sure, expressed as yield pressure, P
y
, is de-
termined by the brittleness and the
incorporation of the polymer.
ACKNOWLEDGMENT
K. K. thanks the Greek State Scholarships’ Foun-
dation for the award of a scholarship.
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AGGLOMERATION OF IBUPROFEN 259
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 89, NO. 2, FEBRUARY 2000
Page 10
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